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International audience; Kidney transplant survival is shortened by chronic rejection and side effects of standard immunosuppressive drugs. Cell-based immunotherapy with tolerogenic dendritic cells has long been recognized as a promising approach to reduce general immunosuppression. Published trials report the safety and the absence of therapy-related adverse reactions in patients treated with tolerogenic dendritic cells suffering from several inflammatory diseases. Here, we present the first phase I clinical trial results using human autologous tolerogenic dendritic cells (ATDC) in kidney transplantation. Eight patients received ATDC the day before transplantation in conjunction with standard steroids, mycophenolate mofetil and tacrolimus immunosuppression with an option to taper mycophenolate mofetil. ATDC preparations were manufactured in a Good Manufacturing Practice-compliant facility and fulfilled cell count, viability, purity and identity criteria for release. A control group of nine patients received the same standard immunosuppression, except basiliximab induction replaced ATDC therapy and mycophenolate tapering was not allowed. During the three-year follow-up, no deaths occurred and there was 100% graft survival. No significant increase of adverse events was associated with ATDC infusion. Episodes of rejection were observed in two patients from the ATDC group and one patient from the control group. However, all rejections were successfully treated by glucocorticoids. Mycophenolate was successfully reduced/stopped in five patients from the ATDC group, allowing tacrolimus monotherapy for two of them. Regarding immune monitoring, reduced CD8 T cell activation markers and increased Foxp3 expression were observed in the ATDC group. Thus, our results demonstrate ATDC administration safety in kidney-transplant recipients.

International audience; No abstract available

Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Inwardly rectifying potassium channel 4.1 is expressed in the central nervous system but also in peripheral tissues, raising concerns about the central nervous system-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino acids 83–120 of Kir4.1) induced anti-e1 immunoglobulin G- and T-cell responses and promoted demyelinating encephalomyelitis with B cell central nervous system enrichment in leptomeninges and T cells/macrophages in central nervous system parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients (n = 252), 6% exhibited high anti-e1 immunoglobulin G levels in serum as compared to 0.7% in the control cohort (n = 127; P = 0.015). Immunolabelling of inwardly rectifying potassium channel 4.1-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation and in multiple sclerosis white matter as compared with controls. Strikingly, the mouse and human anti-e1 sera labelled astrocytoma cells when N-glycosylation was blocked with tunicamycin. Western blot confirmed that neuroinflammation induces Kir4.1 expression, including its shorter aglycosylated form in murine experimental autoencephalomyelitis and multiple sclerosis. In addition, recognition of inwardly rectifying potassium channel 4.1 using mouse anti-e1 serum in Western blot experiments under unreduced conditions or in cells transfected with the N-glycosylation defective N104Q mutant as compared to the wild type further suggests that autoantibodies target an e1 conformational epitope in its aglycosylated form. These data highlight the e1 sequence of inwardly rectifying potassium channel 4.1 as a valid central nervous system autoantigen with a disease/tissue-specific post-translational antigen modification as potential contributor to autoimmunity in some multiple sclerosis patients.

International audience; While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virusassociated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient's underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies.

BACKGROUND AND OBJECTIVES Immune checkpoint inhibitors are increasingly used to treat various malignancies, but their application in patients with kidney transplants is complicated by high allograft rejection rates. Immune checkpoint inhibitor-associated rejection is a novel, poorly understood entity demonstrating overlapping histopathologic features with immune checkpoint inhibitor-associated acute interstitial nephritis, which poses a challenge for diagnosis and clinical management. We sought to improve the understanding of these entities through biopsy-based gene expression analysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS NanoString was used to measure and compare the expression of 725 immune-related genes in 75 archival kidney biopsies, including a 25-sample discovery cohort comprising pure T cell-mediated rejection and immune checkpoint inhibitor-associated acute interstitial nephritis and an independent 50-sample validation cohort comprising immune checkpoint inhibitor-associated acute interstitial nephritis, immune checkpoint inhibitor-associated T cell-mediated rejection, immune checkpoint inhibitor-associated crescentic GN, drug-induced acute interstitial nephritis, BK virus nephropathy, and normal biopsies. RESULTS Significant molecular overlap was observed between immune checkpoint inhibitor-associated acute interstitial nephritis and T cell-mediated rejection. Nevertheless, IFI27, an IFN-α-induced transcript, was identified and validated as a novel biomarker for differentiating immune checkpoint inhibitor-associated T cell-mediated rejection from immune checkpoint inhibitor-associated acute interstitial nephritis (validation cohort: P

International audience; IL‐7 is an important cytokine for T cell lymphopoiesis. Blockade of the IL‐7 signal‐ing pathway has been shown to induce long‐term graft survival or graft tolerance in murine transplant models through inhibiting T cell homeostasis and favoring im ‐munoregulation. In this study, we assessed for the first time the effects of a blocking anti‐human cluster of differentiation 127 (CD127) mAb administered in combination with low‐dose tacrolimus or thymoglobulin in a life‐sustaining kidney allograft model in baboons. Contrary to our expectation, the addition of an anti‐CD127 mAb to the treatment protocols did not prolong graft survival compared to low‐dose tacrolimus alone or thymoglobulin alone. Anti‐CD127 mAb administration led to full CD127 re ‐ceptor occupancy during the follow‐up period. However, all treated animals lost their kidney graft between 1 week and 2 weeks after transplantation. Unlike in rodents, in nonhuman primates, anti‐CD127 mAb treatment does not decrease the absolute numbers of lymphocyte and lymphocyte subsets and does not effectively inhibit postdepletional T cell proliferation and homeostasis, suggesting that IL‐7 is not a lim ‐iting factor for T cell homeostasis in primates.

International audience; Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature hematopoietic precursors known to suppress immune responses. Interaction of SIRP alpha (SIRPα), expressed by myeloid cells, with the ubiquitous receptor CD47 is an important immune checkpoint of the innate response regulating macrophages and dendritic cells functions. We previously described that MDSC expressing SIRPα accumulated after transplantation and maintained kidney allograft tolerance. However, the role of the SIRPα/CD47 axis on MDSC function remained unknown. Here, we found that blocking SIRPα or CD47 with monoclonal antibodies (mAbs) induced differentiation of MDSC into myeloid cells overexpressing MHC class II, CD86 costimulatory molecule and increased secretion of macrophage-recruiting chemokines (eg, MCP-1). Using a model of long-term kidney allograft tolerance sustained by MDSC, we observed that administration of blocking anti-SIRPα or CD47 mAbs induced graft dysfunction and rejection. Loss of tolerance came along with significant decrease of MDSC and increase in MCP-1 concentration in the periphery. Graft histological and transcriptomic analyses revealed an inflammatory (M1) macrophagic signature at rejection associated with overexpression of MCP-1 mRNA and protein in the graft. These findings indicate that the SIRPα-CD47 axis regulates the immature phenotype and chemokine secretion of MDSC and contributes to the induction and the active maintenance of peripheral acquired immune tolerance.

International audience; BACKGROUND:Mild primary hyperparathyroidism (serum calcium ≤ 2.85 mmol/L) is the most representative form of pHPT nowadays. The aim of this study was to evaluate its subtypes and the multiglandular disease (MGD) rate as it may lower the sensitivity of preoperative parathyroid scintigraphy and the surgical cure rate.METHODS:We retrospectively included patients with mild pHPT who underwent parathyroid dual-tracer scintigraphy with 99mTc-MIBI SPECT/CT and surgery between January 2013 and December 2015. Cure was defined as normalization of serum calcium (or PTH in the normocalcemic form) at 6 months. MGD was defined by either two abnormal resected glands or persistent disease after resection of at least one abnormal gland.RESULTS:We included 121 patients. Median preoperative serum calcium was 2.68 mmol/L and median PTH was 83.4 pg/mL. A total of 141 glands were resected (95 adenomas, 33 hyperplasias). The subtypes were 57% classic, 32.2% normohormonal, and 10.7% normocalcemic. MGD occurred in 23.5% of patients divided as 13%, 30%, and 64% respectively (p = 0.0011). The surgical cure rate was 85.2%. The normocalcemic form had lower cure rate than the normohormonal (45% vs 84%, p = 0.018) and classic forms (45% vs 93%, p = 0.0006). MIBI scintigraphy identified at least one abnormal lesion, later confirmed by the pathologist in 90/98 patients, making the sensitivity per patient 91.8% (95% CI 84.1-96.2%).CONCLUSIONS:MGD is strongly associated with mild pHPT, especially the normocalcemic form where it accounts for 64% of cases. Bilateral neck exploration should be performed in this population to improve the cure rate, even if the scintigraphy shows a single focus.

The prognosis of malignant pediatric adrenocortical tumors is closely related to disease stage, which is used to guide perioperative treatment recommendations. However, current scoring systems are inadequate to distinguish between benign and malignant adrenocortical tumors. Robust microscopic prognostic features that could help determine perioperative therapy are also lacking. The aim of this national study was to review the prognostic value of the Wieneke scoring criteria and Ki67 labeling index in unselected pediatric adrenocortical tumors. Using strict definitions previously defined by expert pathologists, a Wieneke score was re-attributed to each tumor after an independent and centralized review. In addition, Ki67 proliferation index was performed and reviewed for each case. A total of 95 cases were selected; all were treated between 2000 and 2018 and had histopathologic material and sufficient outcome-related information available. Localized disease was found in 88% of patients. Among those with advanced disease, 6% had tumor extension into adjacent organs and 5% had metastases at diagnosis. Median follow-up was 5 years and 3 months. The 5-year PFS was 82%, 95% CI [73%-91%]. Tumor stage significantly correlated with PFS (p 0.0001). Tumor weight up to 200 g, extra-adrenal extension and initial non-complete surgical resection were statistically associated with worse outcomes. No recurrences nor metastases occurred when the Ki67 index was 15%. Up to two of the following five factors including tumor necrosis, adrenal capsular invasion, venous invasion, mitotic count 15/20 high-power fields, and Ki67 index 15%, significantly correlated with worse outcomes. We propose a pathological scoring system incorporating the Ki67 index as part of a two-step approach after disease staging to guide adjuvant treatment in pediatric adrenocortical tumors, especially after incomplete resection. These results should be validated in an independent cohort.

The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney transplant recipients (KTRs) and hematopoietic stem cell transplant recipients. In KTRs, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDCs) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived dendritic cells (MDDCs), an in vitro model for mDCs, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDCs. Endocytosed virions were efficiently transmitted to permissive cells and protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c+ mDCs from the blood and kidney parenchyma behaved similarly to MDDCs thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c+ mDC involvement in the BKPyV infection as a promoter of viral spreading., Author summary Dr Sylvia Gardner first discovered the BK polyomavirus (BKPyV) in the urine of a kidney-transplant recipient in 1970. In the 1990’s, the widespread use of potent immunosuppressive drugs such as tacrolimus, sirolimus or mycophenolate mofetil led to the emergence of BKPyV nephropathy. Recently, various studies reported a specific influx of myeloid dendritic cells (mDCs) in the renal tissue of kidney-transplant patients who were diagnosed with a BKPyV nephropathy. MDCs are immune cells both residing in tissues and migrating to other organs or compartments like the blood when changes in their environment occur. Their main functions are the detection of danger signals such as pathogens or tumors and the processing of antigens to prime naïve specific effectors of the adaptive immune response. Although anti-BKPyV cellular immune responses have been investigated in post-transplant recipients as well as healthy individuals, supporting an active role of mDCs little is known about how mDCs and BKPyV interact with each other. Our study provides the basis to understand the role played by mDCs in virus capture through an unprecedented endocytic mechanism and possibly in viral protection from neutralization by specific antibodies. Moreover, we showed that mDCs are unable to sense BKPyV particles or BKPyV-infected dying cells as a danger signal, supporting the view that other DC subsets might act as the true antigen presenting cells that promote the adaptive immune response against BKPyV infection.

e16558 Background: Voided urinary cytology is a non-invasive test, but it suffers from a lack of sensitivity (Se), particularly in low-grade urothelial lesions, and it remains pathologist-dependent. In order to improve the performance of urinary cytopathology, the VitaDX company (France) developed a medical device which uses whole-slide digitalization and artificial intelligence algorithms to identify tumor cells. The device allows complete analysis of morphological characters of voided urothelial cells, such as the shape, size and color of the nuclei. Methods: VISIOCYT1 is a prospective, multicenter clinical trial involving 319 patients divided into two groups: 1) patients with non-muscle invasive bladder tumors (NMIBC) confirmed by histology, and 2) control patients with negative urinary cytology and cystoscopy. The primary objective of the study was to evaluate the Se of the VisioCyt test. Specificity (Sp) and comparison of Se and Sp of conventional urinary cytology vs. the VisioCyt test were also calculated. Results: A total of 319 patients were included (170 in the NIMBC group vs. 149 controls). Overall Se was 80.9% and 45.9% for VisioCyt test and conventional urinary cytology, respectively (p = .002). Negative cytology being an inclusion criterion, a 100% Sp was attributed to the control group. It was calculated at 61.8% for the VisioCyt test. Concerning grade, the VisioCyt test allowed higher Se to be obtained in the low grade tumor category (66.7% vs. 26.1% for conventional urinary cytology, Mc Nemar test, p < .0001). A higher Se was also observed in high grade tumors: 93.7% vs. 62.8% (p < .0001). Conclusions: The VisioCyt test greatly improves the performance of urinary cytopathology in the diagnosis of urothelial bladder tumors, particularly in low grade, pTa lesions. Its implementation could dramatically reduce the need for cystoscopy in patients followed after conservative treatment of bladder cancer. Clinical trial information: NCT02966691. [Table: see text]

The standard technique for pancreas preservation for transplantation is static cold storage (SCS). In this experimental study, we compare SCS to hypothermic machine perfusion (HMP) of the pancreas to assess if the latter could safely prolong the ischaemia period prior to transplantation. We worked in two phases, first with organ preservation for 24 h and second, preservation for either 2 or 6 h before allotransplantation. In phase 1, exocrine injury markers were found to be nonsignificantly lower, in the HMP group (n = 3) vs. SCS (n = 3) after 24 h of preservation; amylase (P = 0.2), lipase (P = 0.3) and lactate dehydrogenase (P = 0.1). In phase 2, 14 recipient diabetic pigs (after total pancreatectomy) received allotransplantations with n = 4 and n = 4 pancreases after HMP for 2 and 6 h vs. n = 3 and n = 3 pancreases after SCS for 2 and 6 h, respectively. There were no differences in recipient survival (P = 0.7), and mean survival was 14 days (0-53 days). All recipients had allograft function defined as detectable C-peptide and independent normoglycemia. We have not highlighted vascular thrombosis in all allotransplantations. This study reports the first successful pancreas allotransplantation after HMP preservation for up to 6 h with no evidence of graft thrombosis.

The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney (KTR) and hematopoietic stem cell transplant recipients. In KTR, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDC) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived DC (MDDC), an in vitro model for mDC, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDC. Endocytosed virions were efficiently transmitted to permissive cells and shown to be protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c+ mDC from the blood and kidney parenchyma behaved similarly to MDDC thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c+ mDC involvement in the BKPyV infection as a promoter of viral spreading.

Context The behavior of locally advanced pheochromocytoma (LAP) remains unknown. Objective We characterized the population with LAP and recurrence-free survival (RFS). Methods This retrospective multicentric study was run within the ENDOCAN-COMETE network and French Group of Endocrine Tumors (GTE) from 2003 to 2018, including patients from 11 French referral centers with LAP as defined by capsular invasion, vascular invasion, adipose tissue invasion, and/or positive locoregional lymph nodes at diagnosis without evidence of distant metastasis. The main outcome measure was recurrence, defined as tumor reappearance, including local site and/or distant metastasis. The primary endpoint was RFS analysis; secondary endpoints were characterization, overall survival (OS), and prognostic factors of recurrence. Results Among 950 patients, 90 (9%) exhibited LAP criteria and 55 met inclusion criteria (median age, 53 years; 61% males; 14% with germline mutation; 84% with catecholamine excess). LAP was defined by 31 (56%) capsular invasions, 27 (49%) fat invasions, 6 (11%) positive lymph nodes, and 22 (40%) vascular invasions. After median follow-up of 54 months (range, 6-180), 12 patients (22%) had recurrences and 3 (5%) died of metastatic disease. Median RFS was 115 months (range, 6-168). Recurrences were local in 2 patients, distant in 2, and both local and distant in 8 patients. Median OS of patients was not reached. Size above 6.5 cm (P = 0.019) and Ki-67 > 2% (P = 0.028) were identified as independent significant prognostic factors in multivariate analysis. Conclusion LAP represents 9% of pheochromocytoma’s population and has a metastatic behavior. This study paves the way for future pathological TNM classification.

International audience; Objectives: The main objective of this experimental study was to evaluate the feasibility of diabetes induction by total pancreatectomy and pancreatic allotransplant after diabetes induction by total pancreatectomy. The secondary objective was to evaluate metabolic (C-peptide, glycemia) and inflammatory (lactate and platelet levels) parameters after diabetes induction by total pancreatectomy and pancreatic allotransplant after total pancreatectomy. Materials and Methods: The study protocol wasapproved by the French Minister of Research (APAFiS no.18169). Insulin-dependent diabetes was induced bytotal pancreatectomy in one male Susscrofa pig, and pancreatic allotransplant was performed, after total pancreatectomy, in 3 male Susscrofa pigs. Total pancreatectomy was performed under general anesthesia, with meticulous dissection of the portal veinand the splenic vein to preserve the spleen. Concerning pancreas procurement, extensive pancreas preparation occurred during the warm phase, before cold perfusion. Pancreatic allotransplant was performed using donor aorta (with superior mesenteric artery and celiactrunk).Results: Diabetes induction was successful, with negative C-peptide values at 3 hours after total pancreatectomy. Glycemic control without hypoglycemic events was obtained with the use of long-acting insulin administered once per day. No rapid-acting insulin was used. In animals that received pancreatic allotransplant, after enteral feeding was started, glycemic control without hypoglycemic events and without insulin was obtained in 2 animals.Conclusions: In an experimental porcine model, diabetes induction by total pancreatectomy and pancreatic allotransplant after total pancreatectomy are feasible and effective. The development of these models offers the potential for new investigations into ischemia-reperfusion injuries, improvement of pancreas procurement methods, and preservation techniques.

Background Infection-related glomerulonephritis with IgA deposits (IRGN-IgA) is a rare disease but it is increasingly reported in the literature. Data regarding epidemiology and outcome are lacking, especially in Europe. We aimed to assess the clinical, pathologic and outcome data of IRGN-IgA. Methods Clinical and outcome data from patients from 11 French centers over the 2007–2017 period were collected retrospectively. We reviewed pathologic patterns and immunofluorescence of renal biopsies and evaluated C4d expression in IRGN-IgA. We analyzed the correlation between histological presentation and outcome. Results Twenty-seven patients (23 men, mean age: 62 ± 15 years) were included. Twenty-one (78%) had Staphylococcus aureus infection and twelve (44%) were diabetic. At the time of biopsy, 95.2% had haematuria, 48.1% had a serum creatinine level of > 4 mg/dL, and 16% had hypocomplementemia. The most common pathologic presentation included mesangial (88.9%) and endocapillary proliferative glomerulonephritis (88.9%) with interstitial fibrosis and tubular atrophy (IF/TA) (85.1%). Diffuse and global glomerular C4d expression was found in 17.8%, mostly in biopsies with acute or subacute patterns, and was associated with a short delay between infection and renal biopsy compared to segmental and focal staining. After median follow-up of 13.2 months, 23.1% died, 46.2% had persistent renal dysfunction and 15.4% reached end-stage renal disease. Renal outcome was correlated to IF/TA severity. Conclusions Infection-related glomerulonephritis with IgA deposits is usually associated with Staphylococcus infections and mainly affects adult men. This entity has a poor prognosis which is correlated to interstitial fibrosis and tubular atrophy severity.

Pancreas transplant longevity is limited by immune rejection, which is diagnosed by graft biopsy using the Banff Classification. The histological criteria for antibody-mediated rejection (AMR) are poorly reproducible and inconsistently associated with outcome. We hypothesized that a 34-gene set associated with antibody-mediated rejection in other solid organ transplants could improve diagnosis in pancreas grafts. The AMR 34-gene set, comprising endothelial, natural killer cell and inflammatory genes, was quantified using the NanoString platform in 52 formalin-fixed, paraffin-embedded pancreas transplant biopsies from 41 patients: 15 with pure AMR or mixed rejection, 22 with T cell-mediated rejection/borderline and 15 without rejection. The AMR 34-gene set was significantly increased in pure AMR and mixed rejection (P = .001) vs no rejection. The gene set predicted histological AMR with an area under the receiver operating characteristic curve (ROC AUC) of 0.714 (P = .004). The AMR 34-gene set was the only biopsy feature significantly predictive of allograft failure in univariate analysis (P = .048). Adding gene expression to DSA and histology increased ROC AUC for the prediction of failure from 0.736 to 0.770, but this difference did not meet statistical significance. In conclusion, assessment of transcripts has the potential to improve diagnosis and outcome prediction in pancreas graft biopsies.

Background Infection-related glomerulonephritis with IgA deposits (IRGN-IgA) is being more widely recognized but the precise epidemiology and outcome is lacking, particularly in Europe. We aimed to assess clinical, pathologic and outcome data of IRGN-IgA. Methods Clinical and outcome data from patients from 11 French centers over the 2007-2017 period were retrospectively collected. We reviewed pathologic patterns and immunofluorescence of renal biopsies and evaluated C4d expression in IRGN-IgA. We analyzed correlation between histological presentation and outcome using the Chi square test (qualitative data) and Kruskal-Wallis test (quantitative data). Results Twenty-seven patients (23 men, mean age: 62 ± 15 years) were included. Most of them had a Staphylococcus aureus infection (77.8%) and 44.4% were diabetic. At the time of biopsy, 95.2% had haematuria, 48.1% had a serum creatinine >4 mg/dL, and 16% had a hypocomplementemia. The most common pathologic presentation included mesangial (88.9%) and endocapillary proliferative glomerulonephritis (88.9%) with interstitial fibrosis with tubular atrophy (IF/TA) (85.1%). Diffuse and global glomerular C4d expression, found in 17.8% of the cases, was most frequently observed in biopsies with acute or subacute pattern and associated with a shorter delay between infection and renal biopsy compared to segmental and focal staining. After a median follow-up of 13.2 months, 23.1% died, 46.2% had persistent renal dysfunction and 15.4% reached end-stage renal disease. Renal outcome was correlated to IF/TA severity. Conclusions Infection-related glomerulonephritis with IgA deposits is usually associated with Staphyloccus infections and mainly affects adult men. This entity has a poor prognosis which is correlated to interstitial fibrosis and tubular atrophy severity.

Introduction Les glomerulonephrites necrosantes pauci-immunes (GNPI) a ANCA negatifs sont generalement associees a la presence d’anticorps dirige contre le cytoplasme des polynucleaires neutrophiles (ANCA) de specificite anti-myeloperoxidase (MPO) et/ou proteinase 3 (PR3). Cependant, une minorite (2–3 %) des patients ayant une GNPI n’ont pas d’ANCA anti-MPO/PR3 detecte. Nous avons etudie le spectre clinique, les caracteristiques histologiques et l’evolution des patients ayant une GNPI a ANCA negatif. Description Serie de cas. Methodes Il s’agissait d’une etude retrospective nationale portant sur 19 centres francais. La GNPI etait definie par la presence de lesions de necroses glomerulaires (croissant et/ou necrose fibrinoide) en l’absence de depot immuns significatifs sur l’etude en immunofluorescence d’immunoglobuline ou de complement. L’absence d’ANCA etait defini par un resultat negatif en immunofluorescence indirecte pour c/p ANCA, l’absence de MPO/PR3 ANCA en ELISA ou en immunoDOT. Les dossiers medicaux ont ete analyse et une deuxieme evaluation des biopsies renale etait realisee pour chaque cas. Resultats Soixante-quatorze patient ayant une GNPI a ANCA negatif ont ete inclus. L’âge median etait de 69 ans. Les caracteristiques cliniques et histologiques au diagnostic etaient marquees par une atteinte extra renale dans 54 % des cas, un syndrome nephrotique dans 32 % des cas et d’une hyper-cellularite endo-capillaire dans 31 % des cas. Trois sous-types ont ete identifie, les formes associees aux infections (12 %), les formes associees aux neoplasies (8 %) et les formes primitives (77 %). Apres une duree de suivi mediane de 28 mois, l’evolution etait marquee par le deces dans 38 % des cas et par l’insuffisance renale terminale dans 27 % des cas. Onze (21 %) patients ont rechute. Conclusion Parmi le spectre clinique des GNPI a ANCA negatifs, les formes associees aux infections et aux neoplasies representent un sous-groupe de patient necessitant une prise en charge specifique. Les GNPI a ANCA negatives sont marquees par une morbi-mortalite importante.

Tacrolimus, the cornerstone immunosuppression after simultaneous pancreas and -kidney (SPK) transplantation, may exert nephrotoxic and diabetogenic effects. We therefore prospectively compared in an open-label, randomized, monocentric, 5-year follow-up study, a tacrolimus- and a sirolimus-based immunosuppressive regimen. Randomization using the block method allowing a blind allocation was done at the time of surgery. All patients received anti-thymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids. At month 3, tacrolimus was continued or replaced by sirolimus. The primary endpoint was kidney and pancreas graft survival at 1 and 5 years. Fifty patients were included in the final analysis in each group. At 1 year, differences for kidney and pancreas graft survival between sirolimus and tacrolimus were 0% (90% confidence interval -4.61% to 4.61%) and 6% (90% confidence interval -6.32% to 18.32%), respectively. There was no difference in renal and pancreas graft survival at 5 years. Thirty-four patients (68%) in the sirolimus group vs three (6%) in the tacrolimus group needed definitive withdrawal of the study drug. Despite noninferiority of sirolimus compared to tacrolimus for kidney and pancreas graft survival, the high rate of sirolimus discontinuation does not favor its use as cornerstone therapy after SPK transplantation (NCT00693446).

International audience; Pancreatic static cold storage (SCS) is the gold-standard method for pancreas preservation. Our main objective was to evaluate feasibility of hypothermic perfusion (HP) of nonhuman primates' pancreases for potential organ transplantation. Seven baboon pancreases were tested. Animals were included in a study approved by the French Research Ministry of Health. Two groups were compared: the control group (n = 2) was preserved using conventional SCS for 24-h and the perfusion group (n = 5) used HP for 24-h, with three different perfusion pressures (PP): 15 (n = 3), 20 (n = 1), and 25 mm Hg (n = 1). In the control group, focal congestion of islets was observed after 6-h. At 24-h, ischemic necrosis and multifocal congestion also occurred. In the HP group, at 15 mm Hg PP, multifocal congestion of islets was present at 24-h. At 20 mm Hg PP, no ischemic necrosis was found after 6-h. At 12-h and 24-h, focal congestion of islets was seen. At 25 mm Hg PP, focal congestion of islets appeared after 12-h. Immunostaining for insulin, glucagon, and somatostatin was normal and similar in controls and perfused pancreas transplants even after 24-h. Apoptosis index represented by cleaved caspase 3 activity, was less than 1% in perfusion and control groups, even after 24-h. HP of nonhuman primate pancreas is feasible and not deleterious as far as 24-h compared to SCS. SCS for more than 12-h was harmful for the transplants. Systolic perfusion pressure between 15-20 mm Hg did not cause any pathological injury of the tested organs.

International audience; Surveillance biopsies after renal transplantation remain debatable. To drive the decision of such intervention, we propose a predictive score of abnormal histology at 1-year post-transplantation, named 1-year Renal Biopsy Index (1-RBI). We studied 466 kidney recipients from the DIVAT cohort alive with a functioning graft and a surveillance biopsy at 1-year post-transplantation. Patients displaying abnormal histology (49%) (borderline, acute rejection, interstitial fibrosis and tubular atrophy [IFTA] grade 2 or 3, glomerulonephritis) were compared to the normal or subnormal (IFTA grade 1) histology group. Obtained from a lasso penalized logistic regression , the 1-RBI was composed of recipient gender, serum creatinine at 3, 6, and 12 month post-transplantation and anticlass II immunization at transplantation (internal validation: AUC = 0.71, 95% CI [0.53-0.83]; external validation: AUC = 0.62, 95% CI [0.58-0.66]). While we could not determinate a threshold able to identify patients at high chance of normal or subnormal histology, we estimated and validated a discriminating threshold capable of identifying a subgroup of 15% of the patients with a risk of abnormal histology higher than 80%. The 1-RBI is computable online at www.divat.fr. The 1-RBI could be a useful tool to standardize 1-year biopsy proposal and may for instance help to indicate one in case of high risk of abnormal histology.

International audience; Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab9 antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preex-isting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.

Anti–programmed cell death 1 (PD-1) antibodies have demonstrated anticancer activities and survival benefit but, because of their mechanism of action, have been associated with autoimmune and alloimmune adverse events.1 We report the case of a kidney transplant patient who presented autoimmune hemol

International audience; Background - Genetic and nutritional factors have been linked to the risk of aggressive prostate cancer (PCa). The fatty acid (FA) composition of peri-prostatic adipose tissue (PPAT), which reflects the past FA intake, is potentially involved in PCa progression. We analysed the FA composition of PPAT, in correlation with the ethno-geographical origin of the patients and markers of tumour aggressiveness. Methods - From a cohort of 1000 men treated for PCa by radical prostatectomy, FA composition of PPAT was analysed in 156 patients (106 Caucasians and 50 African-Caribbeans), 78 with an indolent tumour (ISUP group 1 + pT2 + PSA

International audience; Oncocytic adrenocortical tumors are a rare subtype of adrenal tumors with challenging diagnosis and histoprognostic assessment. It is usually believed that oncocytic adrenocortical tumors have a more indolent clinical behavior than conventional adrenocortical tumors. As the Weiss score overestimates the malignancy of oncocytic adrenocortical tumors owing to intrinsic parameters, alternative scores have been proposed. The Lin-Weiss-Bisceglia score is currently recommended. We performed a large nationwide multicenter retrospective clinicopathologic study of oncocytic adrenocortical tumors. Among the 43 patients in our cohort, 40 patients were alive without disease, 2 patients died of their disease and 1 patient was alive with relapse after a median follow-up of 38 months (20-59). Our data revealed that over 50% of the oncocytic adrenocortical tumor cases were diagnosed as carcinoma whatever the classification systems used, including the Lin-Weiss-Bisceglia score. The exception is the Helsinki score, which incorporates the Ki-67 proliferation index and was the most specific prognostic score for oncocytic adrenocortical tumor malignancy without showing a loss in sensitivity. A comparison of malignant oncocytic adrenocortical tumors with conventional adrenocortical carcinomas matched for age, sex, ENS@T stage and surgical resection status showed significant better overall survival of malignant oncocytic adrenocortical tumors.

Objectifs Les objectifs etaient de mettre au point un modele porcin diabetique par pancreatectomie totale ainsi qu’un modele d’allotransplantation pancreatique sur porc diabetique, apres perfusion pulsatile hypothermique (PH). Methodes L’etude a ete approuve par le ministere de la Recherche (APAFiS #15169). L’induction du diabete par pancreatectomie totale a ete realise chez 1 animal et 11 allotransplantations (alloTx) pancreatiques ont ete realise, avec differentes periodes et techniques de conservation du transplant: groupe controle (n = 2): alloTx apres conservation statique hypothermique (CSH) pendant 2 h, groupe statique 6 h (n = 2): alloTx apres CSH pendant 6 h, groupe perfusion 2 h (n = 4): alloTx apres PH pendant 2 h et groupe perfusion 6 h (n = 3): alloTx apres PH pendant 6 h. Une analyse histologique et biologique a ete realise au cours de la perfusion, apres pancreatectomie et apres transplantation pancreatique. Resultats L’induction du modele diabetique par pancreatectomie totale a ete realise chez un animal. Apres pancreatectomie totale, le taux de peptide C est devenu nul, preuve de l’efficacite du modele. Le taux de fonction du transplant apres alloTx avec CS et PH etait de 80 %. Deux deces en postoperatoire immediat sont survenus dans les groupes perfusion 2 h et 6 h: 1 sur hemorragie et 1 sur ischemie mesenterique apres reprise chirurgicale. Un rejet est survenu dans le groupe controle. Conclusion L’allotransplantation pancreatique sur porc diabetique apres PH est realisable. L’utilisation des machines de perfusion en transplantation pancreatique pourrait permettre de diminuer le taux de complications postoperatoire precoces.

Introduction Les rejets chroniques grevent la survie au long terme des greffons renaux ; prevenir la survenue de ces atteintes est un enjeu majeur, car elles sont irreversibles. Methodes L’objectif de notre travail etait la recherche d’une correlation entre un phenotype lymphocytaire sanguin peripherique, realisable en routine clinique, et l’histologie de la biopsie de greffon. Nous avons analyse en cytometrie de flux les phenotypes lymphocytaires CD8+CD28− cytotoxiques, decrits associes aux rejets chroniques dans des etudes de petits effectifs, ainsi que les LT regulateurs CD4+CD25highCD127. Nous avons realise une cohorte prospective de patients transplantes renaux ayant beneficie d’un immunophenotypage lymphocytaire sanguin le jour de leur biopsie de greffon (realisee en routine : surveillance a 3 et 12 mois ou devant une degradation de la fonction du greffon). Les resultats histologiques ont ete classes en 9 categories basees sur la classification Banff 2015 : normale, subnormale, rejet humoral, suspicion de rejet humoral, rejet cellulaire, lesions borderlines, fibrose interstitielle avec et sans inflammation, autres diagnostics. Resultats obtenus ou attendus Entre 2008 et 2016, 1097 patients ont ete inclus, 1640 biopsies associees a l’immunophenotypage des LT CD8+CD28− et des LT CD4+CD25highCD127 ont ete analysees. En analyse multivariee nous avons demontre que toute augmentation de 10 % du taux de LT CD8 + CD28− sanguin peripherique etait associee a des lesions histologiques borderlines (OR = 1,40 IC 95 [1,1–1,8] par rapport aux biopsies normales). Nous n’avons pas mis en evidence de difference concernant la population LT regulateurs. Conclusion Nous avons demontre que le phenotype lymphocytaire circulant est associe au diagnostic histologique. L’objectif est maintenant d’etablir si le phenotype LT CD8 + CD28− permettrait de differencier au sein des lesions borderline celles de mauvais pronostic necessitant une intensification therapeutique, des lesions histologiques non deleteres. Le phenotype CD8 + CD28− realisable en routine pourrait s’inscrire dans la surveillance des patients transplantes renaux et constituer un signal d’alerte de risque de rejet.

We report the case of a patient affected by a voluminous prostatic tumor for which the histological analysis conclude in a stromal tumor of uncertain malignant potential. This type of tumor is rare, but requires to be individualized to differentiate it from a benign prostatic hyperplasia or a sarcoma of the prostate. The therapeutic care must be made keeping in mind the risk of degeneration towards a malignant shape.

Objectifs L’objectif etait d’evaluer la faisabilite de la perfusion pulsatile hypothermique (PPH) de pancreas de primates non humains pour une potentielle transplantation d’organes. Methodes Sept pancreas de babouins ont ete evalues, apres euthanasie. Ces animaux ont ete inclus dans une etude approuvee par le ministere francais de la Sante. Deux groupes ont ete compares : le groupe temoin (n = 2) a ete preserve en utilisant une conservation statique conventionnelle (SCS) pendant 24 heures et le groupe perfusion (n = 5) a utilise la PPH pendant 24 heures, avec 3 pressions de perfusion (PP) differentes : 15 (n = 3), 20 (n = 1) et 25 mmHg (n = 1). Resultats Dans le groupe temoin, une congestion focale des ilots a ete observee apres 6 heures. A 24 h, une necrose ischemique et une congestion multifocale sont apparues. Dans le groupe perfusion, a 15 mmHg PP, une congestion multifocale des ilots etait presente a 24 heures. A 20 mmHg PP, aucune necrose ischemique n’a ete trouvee apres 6 heures. A 12 h et 24 h, une congestion focale des ilots est apparue. A 25 mmHg PP, la congestion focale des ilots est apparue apres 12 heures. L’immunohistochimie pour l’insuline, le glucagon et la somatostatine etait normale et similaire chez les temoins et les pancreas perfuses, meme apres 24 heures. Conclusion La perfusion pulsatile hypothermique du pancreas de primate non humain est faisable et n’est pas deletere jusqu’a 24 heures par rapport au SCS. La pression systolique de perfusion comprise entre 15–25 mmHg n’a cause aucune lesion pathologique aux organes testes.